7-(1-Pyrrolidinyl)-quinolonecarboxylic acid derivatives

ABSTRACT

7-(1-Pyrrolidinyl)-3-quinolonecarboxylic acid derivatives of the formula   &lt;IMAGE&gt;   in which A is CH, CCl, CF or N, R1 is hydroxyl, hydroxymethyl or mercapto and R2 is hydrogen, alkyl, having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, with the proviso that, when R1 is hydroxy, A is not CF or N, or pharmaceutically acceptable hydrates, or salts thereof, are useful as antibacterials and animal feed utilization promoters.

The present invention relates to new7-(1-pyrrolidinyl)-3-quinolonecarboxylic acid derivatives, to processesfor their preparation and to antibacterial agents and fodder additivescontaining them.

It has already been disclosed that1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid (ciprofloxacin, DE-OS (German Published Specification) No.3,142,854) and8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolonecarboxylicacids (application Ser. No. 735,500, filed May 17, 1985, now pending)are highly active antibacterial agents.

It has now been found that the new7-(1-pyrrolidinyl)-3-quinolonecarboxylic acid derivatives of the formula(I) ##STR2## in which A stands for CH, CCl, CF or N,

R¹ stands for hydroxyl, hydroxymethyl or mercapto and

R² stands for hydrogen, alkyl having 1 to 4 carbon atoms or(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl,

with the proviso that in the case where R¹ stands for hydroxyl A cannotstand for the radical CF or N,

and their pharmaceutically usable hydrates and also the alkali metal,alkaline earth metal, silver and guanidinium salts of the parentcarboxylic acids have a high antibacterial action in the Gram-positiveand Gram-negative range.

They are therefore suitable for use as active compounds for human andveterinary medicine, veterinary medicine also including the treatment offish for the therapy or prevention of bacterial infections.

Preference is given to those compounds of the formula (I) in which

A stands for CH, CCl, CF or N,

R¹ stands for hydroxyl, hydroxymethyl or mercapto and

R² stands for hydrogen, methyl, ethyl, propyl or isopropyl,

with the proviso that in the case where R¹ stands for hydroxyl, A cannotstand for the radical CF or N,

and their pharmaceutically usable hydrates and also the alkali metal,alkaline earth metal, silver and guanidinium salts of the parentcarboxylic acids.

Particular preference is given to those compounds of the formula (I) inwhich

A stands for CH, CCl or CF,

R¹ stands for hydroxyl or hydroxymethyl and

R² stands for hydrogen, methyl or ethyl,

with the proviso that in the case where R¹ stands for hydroxyl A cannotstand for the radical CF,

and their pharmaceutically usable hydrates and also the alkali metal,alkaline earth metal, silver and guanidinium salts of the parentcarboxylic acids.

It has further been found that the compounds of the formula (I) areobtained when compounds of the formula (II) ##STR3## in which A and R²have the abovementioned meaning and

Y stands for halogen, in particular fluorine or chlorine, are reactedwith pyrrolidines of the formula (III) ##STR4## in which R¹ has theabovementioned meaning,

if desired in the presence of acid-binding agents (method A).

Compounds according to the invention of the formula (I) ##STR5## inwhich A, R¹ and R² have the abovementioned meaning but

R² cannot be hydrogen, can also be obtained by reacting a compound (IV)##STR6## in which R¹ and A have the abovementioned meaning,

with compounds of the formula (V)

    R.sup.2 --Z                                                (V)

in which

R² has the abovementioned meaning but cannot be hydrogen, and

Z stands for hydroxyl or halogen, in particular chlorine, bromine oriodine,

if desired in the presence of acid-binding agents or underwater-eliminating conditions (method B).

If in the reaction by method A1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acidand 3-hydroxypyrrolidine are used as starting materials, the course ofreaction can be represented by the following formula diagram: ##STR7##

If in the reaction by method B1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-pyrrolidinyl)-4-oxo-3-quinolinecarboxylicacid and ethyl alcohol are used as starting materials, the course ofreaction can be represented by the following formula diagram: ##STR8##

The compounds of the formula (II) used as starting materials are known.Examples which may be mentioned are:

7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (U.S. Pat. No. 4,670,444),

1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid(European Patent Application No. 113,091),

8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (application Ser. No. 735,500, filed May 17, 1985),

1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (U.S. Pat. No. 4,556,658),

7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyrine-3-carboxylicacid,

ethyl7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate(U.S. Pat. No. 4,670,444),

ethyl1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate(European Patent Application No. 113,091),

ethyl8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate(application Ser. No. 735,500, filed May 17, 1985),

ethyl1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate(U.S. Pat. No. 4,556,658).

The pyrrolidines of the formula (III) used as starting compounds areknown. The compounds can be used not only in the form of racemates butalso in the form of pure enantiomers which can be obtained by widelypracticed methods. The following compounds can be used:

(±)-3-hydroxypyrrolidine,

(+)-3-hydroxypyrrolidine,

(-)-3-hydroxypyrrolidine,

(±)-3-hydroxymethylpyrrolidine,

(+)-3-hydroxymethylpyrrolidine,

(-)-3-hydroxymethylpyrrolidine,

(±)-3-mercaptopyrrolidine,

(+)-3-mercaptopyrrolidine,

(-)-3-mercaptopyrrolidine.

The compounds of the formula (IV) used as starting compounds for methodB are new and are prepared by method A of the process according to theinvention.

The compounds of the formula (V) used as starting compounds are known.Examples which may be mentioned are methanol, ethanol, propanol,isopropanol, butanol, isobutanol, sec.-butanol, tert.-butanol, methyliodide, ethyl bromide, propyl chloride, 4-bromomethyl- or4-chloromethyl-5-methyl-1,3-dioxol-2-one.

The reaction of (II) with (III) using method A, where the pyrrolidines(III) can also be used in the form of their salts, such as, for example,the hydrochlorides, hydrobromides, sulphates or acetates, is preferablycarried out in a diluent such as dimethyl sulphoxide,N,N-dimethylformamide, hexamethylphosphoramide, sulpholane,acetonitrile, water, an alcohol such as methanol, ethanol, n-propanol,isopropanol, glycol monomethyl ether or pyridine. It is also possible touse mixtures of these diluents.

The acid-binders used can be any customary inorganic and organicacid-binding agents. These preferably include the alkali metalhydroxides, alkali metal carbonates, organic amines and amidines.Specific examples of particularly suitable acid-binding agents are:triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) or excess pyrrolidine (III).

The reaction temperatures can be varied within a relatively wide range.In general the process is carried out at between about 20° and 200° C.,preferably between 80° and 180° C.

The reaction can be carried out under atmospheric pressure, and alsounder superatmospheric pressure. In general the process is carried outunder pressures between about 1 and 100 bar, preferably between 1 and 10bar.

In carrying out the process according to the invention, for every moleof carboxylic acid (II) 1 to 15 moles, preferably 1 to 6 moles, of thecompound (III) are used.

Free hydroxyl groups can be protected during the reaction by means of asuitable hydroxyl-protecting group, for example by means of thetetrahydropyranyl radical, and be set free again after the reaction hasended.

To prepare the esters according to the invention by method B, the parentcarboxylic acid of the formula (IV) is converted at temperatures ofabout 20° to 200° C., preferably about 60° to 120° C., preferably inexcess alcohol in the presence of strong acids, such as sulphuric acid,anhydrous hydrogen chloride, methanesulphonic acid, p-toluenesulphonicacid or acidic ion exchangers. The water of reaction formed can also beremoved by azeotropic distillation with chloroform, tetrachloromethane,benzene or toluene.

The alkyl esters can likewise be obtained by reacting an alkali metalsalt or amine salt of the parent carboxylic acid of the formula (IV)with an alkyl halide at temperatures of about 0° C. to about 150° C.,preferably at 10° C. to 100° C., preferably in a diluent such asdimethyl sulphoxide, dimethylformamide, pyridine, sulpholane ortetramethylurea.

The 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl esters used as prodrug areobtained by reacting an alkali metal salt of the parent carboxylic acidwith 4-bromomethyl- or 4-chloromethyl-5-methyl-1,3-dioxol-2-one in asolvent such as dimethylformamide, dimethylacetamide, dimethylsulphoxide or tetramethylurea at temperatures of about 0° C. to 100° C.,preferably 0° C. to 50° C.

The alkali metal or alkaline earth metal salts of the carboxylic acidsaccording to the invention are obtained for example by dissolving theacid in stoichiometrically deficient alkali metal hydroxide or alkalineearth metal hydroxide solution, filtering, and evaporating the filtrateto dryness. The sodium, potassium or calcium salts are pharmaceuticallysuitable. By reacting an alkali metal salt or alkaline earth metal saltwith a suitable silver salt such as silver nitrate, the correspondingsilver salts are obtained.

The active compound according to the invention can be present not onlyas racemates but also as enantiomerically pure compounds.

In addition to the compounds cited in the examples, the following mayspecifically be mentioned as new active compound:

1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(S)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(R)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(S)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(R)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

sodium1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(S)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylate,

potassium1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(R)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylate,

sodium8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(S)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylate,

silver8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(R)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylate,

methyl1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(S)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylate,

ethyl1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(R)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylate,

ethyl8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(S)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylate,

propyl8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(R)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylate,

5-methyl-2-oxo-1,3-dioxol-4-ylmethyl1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(S)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylate,

5-methyl-2-oxo-1,3-dioxol-4-ylmethyl1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(R)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylate,

5-methyl-2-oxo-1,3-dioxol-4-ylmethyl8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(S)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylate,

5-methyl-2-oxo-1,3-dioxol-4-ylmethyl8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(R)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylate,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(S)-hydroxymethyl-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(R)-hydroxymethyl-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(S)-hydroxymethyl-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(R)-hydroxymethyl-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

ethyl1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-hydroxymethyl-1-pyrrolidinyl)-4-oxo-3-quinolinecarboxylate,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxymethyl-1-pyrrolidinyl)-4-oxo-1,8-naphthyridine-3-carboxylicacid,

1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[3-(S)-mercapto-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(R)-mercapto-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(S)-mercapto-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-(R)-mercapto-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-mercapto-1-pyrrolidinyl)-4-oxo-1,8-naphthyridine-3-carboxylicacid.

EXAMPLE OF A TABLET ACCORDING TO THE INVENTION

Each tablet contains:

    ______________________________________                                        Compound of Example 1    583.0  mg                                            Microcrystalline cellulose                                                                             55.0   mg                                            Corn starch              72.0   mg                                            Poly-(1-vinyl-2-pyrrolidone) insoluble                                                                 30.0   mg                                            Highly disperse silicon dioxide                                                                        5.0    mg                                            Magnesium stearate       5.0    mg                                                                     750.0  mg                                            ______________________________________                                    

The lacquer coating contains:

    ______________________________________                                        Poly-(0-hydroxypropyl-0-methyl)-                                                                       6.0    mg                                            cellulose 15 cp                                                               Macrogol 4000 rec. INN   2.0    mg                                            polyethylene glycols (DAB)                                                    Titanium(IV) oxide       2.0    mg                                                                     10.0   mg                                            ______________________________________                                    

The compounds according to the invention exhibit low toxicity and abroad antibacterial spectrum against Gram-positive and Gram-negativeorganisms, in particular against enterobacteriaceae; especiallyincluding those resistant to various antibiotics such as, for example,penicillins, cephalosporins, aminoglycosides, sulphonamides andtetracyclines.

These valuable properties permit their use as chemotherapeutic activecompounds in medicine and as compounds for preserving inorganic andorganic materials, in particular organic materials of all kinds, forexample polymers, lubricants, paints, fibers, leather, paper and timber,foodstuffs and water.

The compounds according to the invention are active against a very broadspectrum of microorganisms. They can be used to combat Gram-negative andGram-positive bacteria and bacteria-like microorganisms and to prevent,ameliorate and/or heal illnesses caused by these pathogens.

The compounds according to the invention are particularly active againstbacteria and bacteria-like microorganisms. They are thereforeparticularly suitable for the prophylaxis and chemotherapy of local andsystemic infections, caused by these pathogens, in human medicine andveterinary medicine.

For example, local and/or systemic illnesses caused by the followingpathogens or by mixtures of the following pathogens can be treatedand/or prevented:

Gram-positive cocci, for example Staphylococci (Staph. aureus and Staph.epidermidis) and Streptococci (Strept. agalactiae, Strept. faecalis,Strept. pneumoniae and Strept. pyogenes); Gram-negative cocci (Neisseriagonorrhoeae) and Gram-negative rods such as Enterobacteriaceae, forexample Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob.freundii, Citrob. divernis), Salmonella and Shigella; also Klebsiellae(Klebs. pneumoniae and Klebs. oxytoca), Enterobacter (Ent. aerogenes andEnt. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr.mirabilis, Pr. rettgeri and Pr. vulgaris), Providencia, Yersinia and thegenus Acinetobacter. The antibacterial spectrum also embraces the genusPseudomonas (Ps. aeruginosa and Ps. maltophilia) and strict anaerobicbacteria such as, for example, Bacteroides fragilis, representatives ofthe genus Peptococcus, Peptostreptococcus and the genus Clostridium;furthermore Mycoplasmae (M. pneumoniae, M. hominis and M. urealyticum)and Mucobacteria, for example Mycobacterium tuberculosis.

The above list of pathogens is purely illustrative and is in no way tobe interpreted as restrictive. The following may be mentioned asexamples of illnesses which are caused by the said pathogens or mixedinfections and which can be prevented, ameliorated and/or healed by thecompounds according to the invention:

Infectious illnesses in humans such as, for example, otitis,pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis,endocarditis, systemic infections, bronchitis (acute or chronic), septicinfections, illnesses of the upper respiratory tract, diffusepanbronchiolitis, pulmonary emphysema, dysentery, enteritis, liverabscesses, urethritis, prostatitis, epididymitis, gastrointestinalinfections, bone and joint infections, cystic fibrosis, skin infections,post-operative wound infections, abscesses, phlegmon, wound infections,infected burns, burns, infections of the mouth, infections followingdental surgery, osteomyelitis, septic arthritis, cholecystitis,peritonitis with appendicitis, cholangitis, intraabdominal abscesses,pancreatitis, sinusitis, mastoiditis, mastitis, tonsillitis, typhoid,meningitis and infections of the nervous system, salpingitis,endometritis, genital infections, pelveoperitonitis and eye infections.

Apart from humans, bacterial infections in other species can also betreated. Examples which may be mentioned are:

pigs: coli diarrhoea, enterotoxaemia, sepsis, dysentery, salmonellosis,mastitis-metritis-agalactia syndrome and mastitis;

ruminants (cattle, sheep and goats): diarrhoea, sepsis,bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis andgenital infections;

horse: bronchopneumonia, joint ill, puerperal and post-puerperalinfections and salmonellosis;

dog and cat: bronchopneumonia, diarrhoea, dermatitis, otitis, urinarytract infections and prostatitis;

poultry (chicken, turkey, quail, pigeon, ornamental birds and others):mycoplasmosis, E. coli infections, chronic respiratory tract illnesses,salmonellosis, pasteurellosis and psittacosis.

It is equally possible to treat bacterial illnesses during rearing andmaintenance of useful and ornamental fish, in which case theantibacterial spectrum is extended beyond the abovementioned pathogensto further pathogens such as, for example, Pasteurella, Brucella,Campylobacter, Listeria, Erysipelothrix, Corynebacteria, Borrelia,Treponema, Nocardia, Rikettsia and Yersinia.

The present invention includes pharmaceutical preparations which, inaddition to non-toxic, inert pharmaceutically suitable excipients,contain one or more compounds according to the invention or whichconsist of one or more active compounds according to the invention, aswell as processes for the manufacture of these preparations.

The present invention also includes pharmaceutical preparation in dosageunits. This means that the preparation is in the form of individualparts, for example tablets, coated tablets, capsules, pills,suppositories and ampules, of which the content of active compoundcorrespond to a fraction or a multiple of an individual dose. The dosageunits can contain, for example, 1, 2, 3 or 4 individual doses or 1/2,1/3 or 1/4 of an individual dose. An individual dose preferably containsthe amount of active compound which is given in one administration andwhich usually corresponds to a whole, a half or a third or a quarter ofa daily dose.

By non-toxic, inert pharmaceutically suitable excipients there are to beunderstood solid, semi-solid or liquid diluents, fillers and formulationauxiliaries of all kinds.

Tablets, coated tablets, capsules, pills, granules, suppositories,solutions, suspensions and emulsions, pastes, ointments, gels, creams,lotions, powders and sprays may be mentioned as preferred pharmaceuticalpreparations.

Tablets, coated tablets, capsules, pills and granules can contain theactive compound or compounds alongside the customary excipients such as(a) fillers and extenders, for example starches, lactose, sucrose,glucose, mannitol and silica, (b) binders, for examplecarboxymethylcellulose, alginates, gelatine and polyvinylpyrrolidone,(c) humectants, for example glycerine, (d) disintegrating agents, forexample agar-agar, calcium carbonate and sodium carbonate, (e) solutionretarders, for example paraffin, and (f) absorption accelerators, forexample quaternary ammonium compounds, (g) wetting agents, for examplecetyl alcohol or glycerine monostearate, (h) adsorbents, for examplekaolin and bentonite, and (i) lubricants, for example talc, calciumstearate and magnesium stearate and solid polyethylene glycols, ormixtures of the substances listed under (a) to (i).

The tablets, coated tablets, capsules, pills and granules can beprovided with the customary coatings and shells, optionally containingopacifying agents, and can also be of such composition that they releasethe active compound or compounds only, or preferentially, in a certainpart of the intestinal tract, optionally in a delayed manner, examplesof embedding compositions which can be used being polymeric substancesand waxes.

The active compound or compounds, optionally together with one or moreof the abovementioned excipients, can also be in a microencapsulatedform.

Suppositories can contain, in addition to the active compound orcompounds, the customary water-soluble or water-insoluble excipients,for example polyethylene glycols, fats, for example cacao fat, andhigher esters (for example C₁₄ -alcohol with C₁₆ -fatty acid) ormixtures of these substances.

Ointments, pastes, creams and gels can contain the customary excipientsin addition to the active compound or compounds, for example animal andvegetable fats, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silica, talcand zinc oxide or mixtures of these substances.

Powders and sprays can contain the customary excipients in addition tothe active compound or compounds, for example lactose, talc, silica,aluminum hydroxide, calcium silicate and polyamide powders or mixturesof these substances. Sprays can additionally contain the customarypropellants, for example chlorofluorohydrocarbons.

Solutions and emulsions can contain the customary excipients in additionto the active compound or compounds, such as solvents, solubilizingagents, and emulsifiers, for example water, ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide,oils, especially cottonseed oil, groundnut oil, corn germ oil, oliveoil, castor oil and sesame oil, glycerine, glycerineformal,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also bein a sterile form which is isotonic with blood.

Suspensions can contain the customary excipients in addition to theactive compound or compounds, such as liquid diluents, for examplewater, ethyl alcohol or propylene glycol, suspending agents, for exampleethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters andsorbitan esters, microcrystalline cellulose, aluminum meta-hydroxide,bentonite, agar-agar and tragacanth or mixtures of these substances.

The formulation forms mentioned can also contain dyestuffs,preservatives and additives which improve the odor and flavor, forexample peppermint oil and eucalyptus oil, and sweeteners, for examplesaccharin.

The therapeutically active compounds should preferably be present in theabovementioned pharmaceutical preparations in a concentration of about0.1 to 99.5, preferably of about 0.5 to 95, percent by weight of thetotal mixture.

The abovementioned pharmaceutical preparations can also contain otherpharmaceutical active compounds in addition to the compounds accordingto the invention.

The abovementioned pharmaceutical preparations are manufactured in theusual manner according to known methods, for example by mixing theactive compound or the active compounds with the excipient orexcipients.

The said preparations can be used in humans and animals either orally,rectally, parenterally (intravenously, intramuscularly orsubcutaneously), intracisternally, intravaginally, intraperitoneally,topically (powder, ointment and drops) and for the therapy of infectionsin hollow spaces and body cavities. Suitable preparations are injectionsolutions, solutions and suspensions for oral therapy, gels, pour-onformulations, emulsions, ointments or drops. It is possible to use fortopical therapy ophthalmological and dermatological formulations, silverand other salts, ear drops, eye ointments, powders or solutions. Inanimals, intake can also be effected via the feed or drinking water insuitable formulations. It is also possible to use gels, oral powders,powders, tablets, retard tablets, premixes, concentrates, granules,pellets, boli, capsules, aerosols, sprays and inhalates in humans andanimals. It is also possible to incorporate the compounds according tothe invention in other excipients such as, for example, plastics(plastic chains for local therapy), collagen or bone cement.

In general it has proved advantageous both in human medicine and inveterinary medicine to administer the active compound or compoundsaccording to the invention in total amounts of about 0.5 to about 500,preferably 5 to 100, mg/kg of body weight every 24 hours, optionally inthe form of several individual administrations, in order to achieve thedesired results. An individual administration contains the activecompound or active compounds according to the invention preferably inamounts of about 1 to about 80, especially of 3 to 30, mg/kg of bodyweight. However, it can be necessary to deviate from the dosagesmentioned and in particular to do so as a function of the nature andbody weight of the subject to be treated, the nature and the severity ofthe illness, the nature of the preparation and of the administration ofthe medicine, and the time or interval over which the administrationtakes place.

Thus it can suffice in some cases to manage with less than theabovementioned amount of active compound while in other cases theabovementioned amount of active compound must be exceeded. Theparticular required optimum dosage and the type of administration of theactive compounds can easily be decided by anyone skilled in the art, onthe basis of his expert knowledge.

The new compounds can be administered, in the usual concentrations andpreparations, together with the feedstuff or the feedstuff preparations,or with the drinking water. It is possible in this way to prevent,ameliorate and/or cure an infection by Gram-negative or Gram-positivebacteria, and hence to achieve an acceleration of growth and animprovement in feedstuff utilization.

The table which follows specifies MIC values for some of the compoundsaccording to the invention, compared with ciprofloxacin.

    ______________________________________                                        MIC values (mg/l)*                                                                        Example                                                           Organisms     1         3       Ciprofloxacin                                 ______________________________________                                        E. coli                                                                       4418          <0.015    ≦0.015                                                                         ≦0.015                                 Neumann       ≦0.015                                                                           ≦0.015                                                                         ≦0.015                                 T7            <0.015    ≦0.015                                                                         ≦0.015                                 455/7         32        0.25    1                                             A261          <0.015    ≦0.015                                                                         ≦0.015                                 Klebsiella pneum.                                                             63            <0.015    ≦0.015                                                                         0.03                                          8085          ≦0.015                                                                           ≦0.015                                                                         ≦0.015                                 6179          0.125     <0.015  0.125                                         57USA         0.125     ≦0.015                                                                         ≦0.015                                 6318          0.06      ≦0.015                                                                         0.06                                          Proteus mir.                                                                  8223          2         0.06    4                                             8175          0.06      ≦0.015                                                                         0.06                                          Proteus vulg.                                                                 1017          ≦0.015                                                                           ≦0.015                                                                         ≦0.015                                 Proteus morg.                                                                 932           ≦0.015                                                                           ≦0.015                                                                         <0.015                                        11006         ≦0.015                                                                           ≦0.015                                                                         ≦0.015                                 Providencia stuartei                                                          12012         ≦0.015                                                                           ≦0.015                                                                         ≦0.015                                 12052         32        1       16                                            Serratia marc.                                                                16040         32        1       8                                             Staph. aureus                                                                 FK422         ≦0.015                                                                           ≦0.015                                                                         0.5                                           1756          ≦0.015                                                                           ≦0.015                                                                         0.25                                          133           ≦0.015                                                                           ≦0.015                                                                         0.25                                          Strepto. faecalis                                                             27101         0.125     ≦0.015                                                                         0.25                                          9790          0.125     ≦0.015                                                                         0.5                                           Psdm. aeruginosa                                                              Walter        1         0.25    0.5                                           Ellsworth     0.125     ≦0.015                                                                         0.06                                          ______________________________________                                         *Agar dilution test (multipoint inoculator) Isosensitest medium pH 7.2   

EXAMPLE 1 ##STR9##

To 7.95 g (30 mmol) of1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acidin a mixture of 60 ml of acetonitrile and 30 ml of dimethylformamide areadded 3.9 g (31 mmol) of 3-hydroxypyrrolidine hydrochloride (racemate)and 9.9 g (88 mmol) of 1,4-diazabicyclo[2.2.2]octane, and the mixture isrefluxed for 3 hours. The suspension is concentrated, the residue isstirred up with about 100 ml of water, and the mixture is brought to pH6-7 with 2N hydrochloric acid. The undissolved reaction product isfiltered off with suction, washed with water and dried.

Yield: 9.3 g (93.3% of theory) of1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-pyrrolidinyl)-4-oxo-3-quinolinecarboxylicacid having a melting point of 325° C.-328° C. (with decomposition).

EXAMPLE 2

2.65 g (10 mmol) of1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acidare heated at 130° C. for 3 hours in 6 ml of dimethyl sulphoxidetogether with 1 g (11 mmol) of 3-hydroxypyrrolidine (racemate) and 2.2 g(20 mmol) of 1,4-diazabicyclo[2.2.2]octane. After cooling down, thesuspension is stirred up with 30 ml of water and brought to pH 6-7 with2N hydrochloric acid, and the precipitate is filtered off with suction,washed with water and boiled up in 30 ml of glycol monomethyl ether.This gives 2.7 g (81% of theory) of1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-pyrrolidinyl)-4-oxo-3-quinolinecarboxylicacid having a melting point of 332°-336° C. (with decomposition).According to thin layer chromatography the compound is identical to thecompound of Example 1.

EXAMPLE 3 ##STR10##

To 1.5 g (5 mmol) of8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid in 10 ml of acetonitrile and 5 ml of dimethylformamide are added1.1 g (10 mmol) of 1,4-diazabicyclo[2.2.2]octane and 650 mg (5.3 mmol)of 3-hydroxypyrrolidine hydrochloride and the mixture is refluxed for 3hours. The suspension is concentrated, the residue is stirred up withwater and brought to pH 6-7 with 2N hydrochloric acid, and theprecipitate is filtered off with suction, dried and recrystallized fromglycol monomethyl ether.

Yield: 1.2 g (65% of theory) of8-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-7-(3-hydroxy-1-pyrrolidinyl)-4-oxo-3-quinolinecarboxylicacid having a melting point of 221°-223° C. (with decomposition).

EXAMPLE 4 ##STR11##

Example 1 is repeated with 3-hydroxymethylpyrrolidine, affording1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxymethyl-1-pyrrolidinyl)-3-quinolinecarboxylicacid having a melting point of 278°-281° C. (with decomposition).

The same method is used to obtain:

8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxymethyl-1-pyrrolidinyl)-3-quinolinecarboxylicacid having a melting point of 160°-162° (with decomposition);

1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-hydroxymethyl-1-pyrrolidinyl)-3-quinolinecarboxylicacid having a melting point of 236°-240° C. (with decomposition).

It will be understood that the specification and examples areillustrative but not limitative of the present invention and that otherembodiments within the spirit and scope of the invention will suggestthemselves to those skilled in the art.

What is claimed is:
 1. A 7-(1-pyrrolidinyl)-3-quinolonecarboxylic acidderivative having the formula ##STR12## in which R¹ is hydroxymethylandR² is hydrogen, or alkyl, having 1 to 4 carbon atoms,or apharmaceutically acceptable hydrate, alkali metal alkaline earth metal,silver or guanidinium salt.
 2. A compound, hydrate or salt according toclaim 1,in which R² is hydrogen, methyl, ethyl, propyl or isopropyl. 3.A compound, hydrate or salt according to claim 1, in whichR² ishydrogen, methyl or ethyl.
 4. A compound according to claim 1, whereinsuch compound is8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxymethyl-1-pyrrolidinyl)-4-oxo-3-quinolinecarboxylicacid of the formula ##STR13## or a pharmaceutically acceptable hydrate,alkali metal, alkaline earth metal, silver or guanidinium salt thereof.5. An antibacterial composition comprising an antibacterially effectiveamount of a compound, hydrate or salt according to claim 1 and apharmaceutically acceptable diluent.
 6. A method of combating bacteriawhich comprises administering to a patient an antibacterially effectiveamount of a compound, hydrate or salt according to claim
 1. 7. Themethod according to claim 6, wherein such compoundis8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxymethyl-1-pyrrolidinyl)-4-oxo-3-quinolinecarboxylicacid,or a pharmaceutically acceptable hydrate, alkali metal, alkalineearth metal, silver or guanidinium salt thereof.
 8. An animal growthpromoting composition comprising an animal growth promoting effectiveamount of a compound, hydrate or salt according to claim 1 and ediblefeed base.
 9. A method of promoting the growth of animals whichcomprises feeding said animals an animal growth promoting effectiveamount of a compound, hydrate or salt according to claim
 1. 10. Themethod according to claim 9, wherein such compoundis8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxymethyl-1-pyrrolidinyl)-4-oxo-3-quinolinecarboxylicacid,or a pharmaceutically acceptable hydrate, alkali metal, alkalineearth metal, silver or guanidinium salt thereof.